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All 11 posts Subject: Discussing the Mannich reaction Please login to post Down

Megatherium
(Hive Bee)
03-23-04 00:33
No 496728
      Discussing the Mannich reaction

High Bees wink ,

I 've been wondering a bit about the general applicability of the Mannich reaction procedure in Patent US6538136. Me thinks this happens in example 2:

Flask 1:
1 mol Bzl-NH₂ + 2,25 eq. CH₂O --> Bzl-NH-CH₂-OH + 1,25 eq. excess CH₂O (don't know if imine will be formed without acid, since the optimal pH for this is 4 - 5)

Flash 2:
1,06 eq. CH₃-CO-CH-CH(CH₃)₂ + 1,11 eq. HCl --> CH₃-COH-C=C(CH₃)₂ + 1,11 eq. HCl (acid catalysed keto-enol equilibrium, notice the thermodynamic enol will be generated predominantly)

Drip flask 1 in flask 2:
Bzl-NH-CH₂-OH + 1,25 eq. excess CH₂O + CH₃-COH-C=C(CH₃)₂ + 1,11 eq. HCl --> iminium ion formed in situ Bzl-NH(+).Cl=CH₂ + H20 & reacts with enol --> Bzl-NH-CH₂-C(CH₃)₂-CO-CH₃ + HCl regenerated & reacts with just formed secundary amine or protonates another aminoalcohol

Add 1,1 eq. iPr₂EtN to freebase the secundary amine --> Bzl-NH-CH₂-C(CH₃)₂-CO-CH₃ + iPr₂EtN.HCl + 1,25 eq. + 0.3 eq.(yeah, why not add some more) CH₂O --> Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃

Now comes the tricky part:
We have Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃, 1,1 eq. iPr₂EtN.HCl (and 0,01 eq. HCl, but in example 1 there is more base used to neutralize the HCl, so no HCl is present, just Et₃N.HCl and 0.05 eq Et₃N) with an excess CH₂0 in a H₂O / EtOH solution

Me thinks the aminoalcohol gets protonated first with the HCl liberated from iPr₂EtN.HCl <__--> iPr₂EtN + HCl. At the same time iPr₂EtN is generated which supposedly abstracts a proton from the CH₃-CO-C(CH₃)₂-R ketone.

Now, the problem with the general applicability of this patent is that a weak base in a protic solvent gives the thermodynamic enolate (the one with the least H 's attatched to it). To generate the 3,3-dimethyl piperidone this is no problem, since only the kinetic enolate can be formed. But with 3-methyl piperidone (and even worse with ordinary piperidone), the wrong enolate will be formed. A sterically hindered base is used, but do you think that will solve the problem of the inherently favored thermodynamic enolate formation? It makes me rather suspicous, since they don't demonstrate the general applicability of the patent with some other examples ... (mabey the yields sucks)

This is how me thinks the reaction proceeds further:
Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃ + iPr₂EtN.HCl --> Bzl-N(+).Cl(=CH₂)-CH₂-C(CH₃)₂-CO-CH₂(-) + iPr₂EtNH(+) --> N-benzyl-3,3-dimethyl-4-piperidone + iPr₂EtN.HCl regenerated

I think an excess of formaldehyde is used to shift the equilibrium in the favorable way, but mabey this isn't a good idea for other piperidones than the 3,3-dimethyl ones.

What do you bees think about the proposed reaction mechanism? It is rather amazing that this all takes place in one pot cool . Do you also forsee problems for other (less 3 substituted) piperidones.

Megatherium
(Hive Bee)
03-23-04 12:22
No 496829
      Another problem

Another problem with this procedure is that primary amines can bee dialkylated. I think this problem is minimized by slowly dripping the aminoalcohol / excess formaldehyde in the ketone / HCl solution ... even though I am wondering whether the excess formaldehyde is really necessary.

Mabey the use of a stoichiometric amount of formaldehyde can solve the problems for the less 3-substituted piperidones. Particulary with the second mannich reaction: freebase the secondary amine, let it react with 1 eq. formaldehyde   --> iminium formation & mabey bring the pH back to 4 - 5. Only the kinetic enol can react with the iminium & no residual CH2O is left in the mixture.

In some chemical encyclopedia, they say that in the reaction (CH₃)₂NH + (CH₃)₂CH-CO-CH₃ + formaldehyde, the thermodynamic product is formed in a 3,5 / 1 ratio, relative to kinetic mannich base (oddly, no further references were given ...). What worries me is: could the (excess) formaldehyde react with the Bzl-N(+).Cl(=CH₂)-CH₂-C(CH₃)=COH-CH₃ or Bzl-N(+).Cl(=CH₂)-CH₂-CH=COH-CH₃ enol (in a 3-methyl-4-piperidone and 4-piperdione synthesis respectively), which will be formed predominantly.

If this reaction could be (made) generally applicable, it would bee the easiest piperidone synthesis up to date.

Are these mechanistic worries justified, or is this bee totally screwing up here? I guess it is all a matter of equilibrium & pH.

Megatherium
(Hive Bee)
03-24-04 01:37
No 496936
      Working towards a solution

Paraformaldehyde is a polymeric acetal which cleaves under acidic conditions.

As I understand it, the reaction is acid catalysed (so the acid will be regenerated). I think it will be favorable to do the reaction in absolute ethanol: due to the equilibria in the iminium formation and le Chatelier ...

But, the dropwise addition of the aminoalcohol to the ketone / acid - ethanol solution is a very good idea, since in this medium:
1) the enol forms (acid catalysed)
2) the aminoalcohol, which is dripped in, is converted in situ to the iminium salt (consumes 1 eq. of acid, but it is regenerated by the addition of the enol to the iminium salt, and the liberated acid is captured then by the formed secundary amine.)
3) the in situ formed imine reacts with an excess of enol. Since no excess formaldehyde is used, dialkylation is less likely to occur

The Mannich reaction on primary amines has been done with paraformaldehyde in ethanol has been done in
Patent DE379950 example 5: I particulary like that one, since equimolar amounts of methylamine.HCl and paraformaldehyde are used in alcohol.
Patent DE542253 example 5

Another inspiring articles are:
http://www.mdpi.org/molbank/m0215.htm
http://www.mdpi.org/molbank/m0217.htm

I guess here the amine salt dissociates and the formaldehyde is formed in situ (grace а the liberated HCl) and the amine reacts with it.
There 's another nice iminium ion formation procedure in: https://www.rhodium.ws/chemistry/amphetamine.methylation.html
(the Freifelder article). Here the iminium salt is generated at last (with a 1 eq. addition of acetic acid). It seems that the amine reacts with the paraformaldehyde even without the addition of acid (but I seem to remember that bases react with the polymeric acetal to a lesser extent than acids).

Would it be a good idea to
1) formation of the aminoalcohol in absolute EtOH, with a bit of acid to catalyze the reaction (trifluoroacetic acid or HCl)
2) add the above solution dropwise to a absolue ethanol solution with (at least 1 eq.) of TFA or HCl

Since the entire process is acid catalysed (please correct me on this if I am wrong), I 'd make sure that the pH is between 4 - 5 when all the aminoalcohol is added.

Don't hesitate to participate in this thread. All replies (critical remarks, other proposed routes, answers towards uncertainties, ...) will be appreciated smile .

Megatherium
(Hive Bee)
03-24-04 14:01
No 497035
      I guess here the amine salt dissociates and...

I guess here the amine salt dissociates and the formaldehyde is formed in situ (grace а the liberated HCl) and the amine reacts with it.

The same methodology is used here (synthesis of mannich bases 6 a - d)

http://www.shd.org.yu/HtDocs/SHD/Vol66/No1/V66-no1-02.pdf
It seems to take some time beefore te acetal gets depolymerisised.

An interesting example of Mannich cyclization is the synthesis of myrtine:
Tetrahedron Letters (1978), p 397 (has to bee checked out).

Megatherium
(Hive Bee)
03-25-04 00:30
No 497114
      Advances in the chemistry of Mannich bases

This sounds like being one of those comprehensive review article, known to give the dedicated chemist an orgasm:

Tramontini,M. Advances in the chemistry of Mannich bases. Synthesis (1973) p 703 - 775

Rhodium
(Chief Bee)
03-25-04 13:48
No 497260
User Picture       Advances in the chemistry of Mannich bases
(Rated as: good read)

Advances in the chemistry of Mannich bases
M. Tramontini
Synthesis 703-775 (1973)

^{The Hive - Clandestine Chemists Without Borders}

ning
(acetaminophanatic)
04-03-04 17:15
No 498883
      AFAIK

AFAIK just putting excess formaldehyde in with your primary amine of choice, acetone (or possibly MEK for 3-me piperidone), and some base does the job. It automatically cyclizes for you. As far as I know.
The MEK might be too hindered for this to work well (I think I remember hearing something to that effect), but I know acetone does. There's some articles in Chemische Berichte and Liebig's Annalen that I can't get on exactly this reaction. I'll have to dig up some refs and post them--maybe someone else can get them.

Catching a buzz @ the Hive

Megatherium
(Hive Bee)
04-04-04 12:36
No 498998
      Hello Ning

There's some articles in Chemische Berichte and Liebig's Annalen that I can't get on exactly this reaction. I'll have to dig up some refs and post them--maybe someone else can get them.

That would be appreciated very much.

Are there references to journals for the reaction scheme, proposed in the Chemistry of Organic Compounds (1951) Pg. 705 ( Post 475766 (ning: "The Big Post", Novel Discourse) )?

Vaaguh
(Hive Bee)
11-08-04 21:53
No 540489
User Picture       Chemistry of Organic Compounds (1951)

Is there an online store that stil sells this book ? I can't seem to find the book anywhere (or the ISBN number).

Hippler

SpicyBrown
(Hive Bee)
11-10-04 02:13
No 540728
      Who's the author(s)? I was able to find the...

Who's the author(s)? I was able to find the following available used:

Chemistry of Organic Compounds
by Carl Robert, Noller
# Publisher: Not Applicable (June, 1965)
# ISBN: 0721668216

Could this be a newer edition of the book you've mentioned?
I also have a few old chemistry books from a ways back; oftentimes, older ones simply don't have ISBN numbers. If they're US-published books, they'll have a library of congress catalog number however.

-SpicyBrown

lugh
(Moderator)
11-11-04 01:49
No 540947
      Page 767 from 1951 edition

There are no references given anywhere in Noller's Chemistry of Organic Compounds from 1951; so it's doubtful if it's worth very much money wink Here's the part of the book ning quoted from:

laugh

Chemistry is our Covalent Bond

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	All 11 posts		Subject: Discussing the Mannich reaction		Please login to post		Down


		Megatherium (Hive Bee) 03-23-04 00:33 No 496728				Discussing the Mannich reaction
						High Bees , I 've been wondering a bit about the general applicability of the Mannich reaction procedure in Patent US6538136. Me thinks this happens in example 2: Flask 1: 1 mol Bzl-NH₂ + 2,25 eq. CH₂O --> Bzl-NH-CH₂-OH + 1,25 eq. excess CH₂O (don't know if imine will be formed without acid, since the optimal pH for this is 4 - 5) Flash 2: 1,06 eq. CH₃-CO-CH-CH(CH₃)₂ + 1,11 eq. HCl --> CH₃-COH-C=C(CH₃)₂ + 1,11 eq. HCl (acid catalysed keto-enol equilibrium, notice the thermodynamic enol will be generated predominantly) Drip flask 1 in flask 2: Bzl-NH-CH₂-OH + 1,25 eq. excess CH₂O + CH₃-COH-C=C(CH₃)₂ + 1,11 eq. HCl --> iminium ion formed in situ Bzl-NH(+).Cl=CH₂ + H20 & reacts with enol --> Bzl-NH-CH₂-C(CH₃)₂-CO-CH₃ + HCl regenerated & reacts with just formed secundary amine or protonates another aminoalcohol Add 1,1 eq. iPr₂EtN to freebase the secundary amine --> Bzl-NH-CH₂-C(CH₃)₂-CO-CH₃ + iPr₂EtN.HCl + 1,25 eq. + 0.3 eq.(yeah, why not add some more) CH₂O --> Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃ Now comes the tricky part: We have Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃, 1,1 eq. iPr₂EtN.HCl (and 0,01 eq. HCl, but in example 1 there is more base used to neutralize the HCl, so no HCl is present, just Et₃N.HCl and 0.05 eq Et₃N) with an excess CH₂0 in a H₂O / EtOH solution Me thinks the aminoalcohol gets protonated first with the HCl liberated from iPr₂EtN.HCl <__--> iPr₂EtN + HCl. At the same time iPr₂EtN is generated which supposedly abstracts a proton from the CH₃-CO-C(CH₃)₂-R ketone. Now, the problem with the general applicability of this patent is that a weak base in a protic solvent gives the thermodynamic enolate (the one with the least H 's attatched to it). To generate the 3,3-dimethyl piperidone this is no problem, since only the kinetic enolate can be formed. But with 3-methyl piperidone (and even worse with ordinary piperidone), the wrong enolate will be formed. A sterically hindered base is used, but do you think that will solve the problem of the inherently favored thermodynamic enolate formation? It makes me rather suspicous, since they don't demonstrate the general applicability of the patent with some other examples ... (mabey the yields sucks) This is how me thinks the reaction proceeds further: Bzl-N(CH₂-OH)-CH₂-C(CH₃)₂-CO-CH₃ + iPr₂EtN.HCl --> Bzl-N(+).Cl(=CH₂)-CH₂-C(CH₃)₂-CO-CH₂(-) + iPr₂EtNH(+) --> N-benzyl-3,3-dimethyl-4-piperidone + iPr₂EtN.HCl regenerated I think an excess of formaldehyde is used to shift the equilibrium in the favorable way, but mabey this isn't a good idea for other piperidones than the 3,3-dimethyl ones. What do you bees think about the proposed reaction mechanism? It is rather amazing that this all takes place in one pot . Do you also forsee problems for other (less 3 substituted) piperidones.



		Megatherium (Hive Bee) 03-23-04 12:22 No 496829				Another problem
						Another problem with this procedure is that primary amines can bee dialkylated. I think this problem is minimized by slowly dripping the aminoalcohol / excess formaldehyde in the ketone / HCl solution ... even though I am wondering whether the excess formaldehyde is really necessary. Mabey the use of a stoichiometric amount of formaldehyde can solve the problems for the less 3-substituted piperidones. Particulary with the second mannich reaction: freebase the secondary amine, let it react with 1 eq. formaldehyde --> iminium formation & mabey bring the pH back to 4 - 5. Only the kinetic enol can react with the iminium & no residual CH2O is left in the mixture. In some chemical encyclopedia, they say that in the reaction (CH₃)₂NH + (CH₃)₂CH-CO-CH₃ + formaldehyde, the thermodynamic product is formed in a 3,5 / 1 ratio, relative to kinetic mannich base (oddly, no further references were given ...). What worries me is: could the (excess) formaldehyde react with the Bzl-N(+).Cl(=CH₂)-CH₂-C(CH₃)=COH-CH₃ or Bzl-N(+).Cl(=CH₂)-CH₂-CH=COH-CH₃ enol (in a 3-methyl-4-piperidone and 4-piperdione synthesis respectively), which will be formed predominantly. If this reaction could be (made) generally applicable, it would bee the easiest piperidone synthesis up to date. Are these mechanistic worries justified, or is this bee totally screwing up here? I guess it is all a matter of equilibrium & pH.



		Megatherium (Hive Bee) 03-24-04 01:37 No 496936				Working towards a solution
						Paraformaldehyde is a polymeric acetal which cleaves under acidic conditions. As I understand it, the reaction is acid catalysed (so the acid will be regenerated). I think it will be favorable to do the reaction in absolute ethanol: due to the equilibria in the iminium formation and le Chatelier ... But, the dropwise addition of the aminoalcohol to the ketone / acid - ethanol solution is a very good idea, since in this medium: 1) the enol forms (acid catalysed) 2) the aminoalcohol, which is dripped in, is converted in situ to the iminium salt (consumes 1 eq. of acid, but it is regenerated by the addition of the enol to the iminium salt, and the liberated acid is captured then by the formed secundary amine.) 3) the in situ formed imine reacts with an excess of enol. Since no excess formaldehyde is used, dialkylation is less likely to occur The Mannich reaction on primary amines has been done with paraformaldehyde in ethanol has been done in Patent DE379950 example 5: I particulary like that one, since equimolar amounts of methylamine.HCl and paraformaldehyde are used in alcohol. Patent DE542253 example 5 Another inspiring articles are: http://www.mdpi.org/molbank/m0215.htm http://www.mdpi.org/molbank/m0217.htm I guess here the amine salt dissociates and the formaldehyde is formed in situ (grace а the liberated HCl) and the amine reacts with it. There 's another nice iminium ion formation procedure in: https://www.rhodium.ws/chemistry/amphetamine.methylation.html (the Freifelder article). Here the iminium salt is generated at last (with a 1 eq. addition of acetic acid). It seems that the amine reacts with the paraformaldehyde even without the addition of acid (but I seem to remember that bases react with the polymeric acetal to a lesser extent than acids). Would it be a good idea to 1) formation of the aminoalcohol in absolute EtOH, with a bit of acid to catalyze the reaction (trifluoroacetic acid or HCl) 2) add the above solution dropwise to a absolue ethanol solution with (at least 1 eq.) of TFA or HCl Since the entire process is acid catalysed (please correct me on this if I am wrong), I 'd make sure that the pH is between 4 - 5 when all the aminoalcohol is added. Don't hesitate to participate in this thread. All replies (critical remarks, other proposed routes, answers towards uncertainties, ...) will be appreciated .



		Megatherium (Hive Bee) 03-24-04 14:01 No 497035				I guess here the amine salt dissociates and...
						I guess here the amine salt dissociates and the formaldehyde is formed in situ (grace а the liberated HCl) and the amine reacts with it. The same methodology is used here (synthesis of mannich bases 6 a - d) http://www.shd.org.yu/HtDocs/SHD/Vol66/No1/V66-no1-02.pdf It seems to take some time beefore te acetal gets depolymerisised. An interesting example of Mannich cyclization is the synthesis of myrtine: Tetrahedron Letters (1978), p 397 (has to bee checked out).



		Megatherium (Hive Bee) 03-25-04 00:30 No 497114				Advances in the chemistry of Mannich bases
						This sounds like being one of those comprehensive review article, known to give the dedicated chemist an orgasm: Tramontini,M. Advances in the chemistry of Mannich bases. Synthesis (1973) p 703 - 775



		Rhodium (Chief Bee) 03-25-04 13:48 No 497260				Advances in the chemistry of Mannich bases (Rated as: good read)
						Advances in the chemistry of Mannich bases M. Tramontini Synthesis 703-775 (1973) ^{The Hive - Clandestine Chemists Without Borders}



		ning (acetaminophanatic) 04-03-04 17:15 No 498883				AFAIK
						AFAIK just putting excess formaldehyde in with your primary amine of choice, acetone (or possibly MEK for 3-me piperidone), and some base does the job. It automatically cyclizes for you. As far as I know. The MEK might be too hindered for this to work well (I think I remember hearing something to that effect), but I know acetone does. There's some articles in Chemische Berichte and Liebig's Annalen that I can't get on exactly this reaction. I'll have to dig up some refs and post them--maybe someone else can get them. Catching a buzz @ the Hive



		Megatherium (Hive Bee) 04-04-04 12:36 No 498998				Hello Ning
						There's some articles in Chemische Berichte and Liebig's Annalen that I can't get on exactly this reaction. I'll have to dig up some refs and post them--maybe someone else can get them. That would be appreciated very much. Are there references to journals for the reaction scheme, proposed in the Chemistry of Organic Compounds (1951) Pg. 705 ( Post 475766 (ning: "The Big Post", Novel Discourse) )?



		Vaaguh (Hive Bee) 11-08-04 21:53 No 540489				Chemistry of Organic Compounds (1951)
						Is there an online store that stil sells this book ? I can't seem to find the book anywhere (or the ISBN number). Hippler



		SpicyBrown (Hive Bee) 11-10-04 02:13 No 540728				Who's the author(s)? I was able to find the...
						Who's the author(s)? I was able to find the following available used: Chemistry of Organic Compounds by Carl Robert, Noller # Publisher: Not Applicable (June, 1965) # ISBN: 0721668216 Could this be a newer edition of the book you've mentioned? I also have a few old chemistry books from a ways back; oftentimes, older ones simply don't have ISBN numbers. If they're US-published books, they'll have a library of congress catalog number however. -SpicyBrown



		lugh (Moderator) 11-11-04 01:49 No 540947				Page 767 from 1951 edition
						There are no references given anywhere in Noller's Chemistry of Organic Compounds from 1951; so it's doubtful if it's worth very much money Here's the part of the book ning quoted from: Chemistry is our Covalent Bond

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